The liver manages a wide range of metabolic functions, which are controlled by interrelated signaling[unreadable] pathways. One such pathway involves cytosolic Ca2+ signaling in hepatocytes, which regulates activities[unreadable] such as bile secretion, glucose metabolism, and cytoskeletal organization. The goal of this Program Project[unreadable] is to examine the mechanisms and effects of a complementary Ca2+ signaling system, within the nucleus of[unreadable] hepatocytes. During the current award it was found that free Ca2+ in the nucleus and cytosol can be[unreadable] controlled separately, and that gene transcription, hepatocyte growth, and development of steatosis are[unreadable] regulated by nuclear Ca2+ through downstream activation of the mitogen-activated protein kinase (MAPK)[unreadable] and MAPK phosphatase-1 (MKP-1) pathways. During the next award period we will test the hypothesis that[unreadable] growth factors regulate liver growth by release of nuclear Ca2+ from inositol 1,4,5-trisphosphate receptors[unreadable] (InsPSRs) that reside on the nucleoplasmic reticulum, and that activation of nuclear Ca2+ signals controls[unreadable] gene expression involved in hepatic growth and regeneration by dynamically acting on both positive (MAPK)[unreadable] and negative (MKP-1) regulatory signaling pathways. This will be tested through the following projects:[unreadable] Project by Nathanson will determine whether and how receptor tyrosine kinases regulate growth of hepatocytes by[unreadable] inducing lnsP3-mediated Ca2+ signals within the nucleus.[unreadable] Project by Ehrlich will investigate whether and how MAPK and the MAPK phosphatase, MKP-1, differentially regulate[unreadable] the function and distribution of nuclear and cytosolic InsPSRs.[unreadable] Project by Bennett will investigate how local Ca2+ signals within the cytosol or nucleus control MKP-1 expression in[unreadable] order to modulate the magnitude and kinetics of gene activity required for liver growth and metabolism.[unreadable] To help carry out these projects, core facilities will be established for cell and molecular biology, cell[unreadable] imaging, and administration. These projects will collectively provide a comprehensive investigation of how[unreadable] nuclear Ca2+ provides a local conduit in the nucleus for the control of MAPK-mediated gene expression in[unreadable] the liver. The results of these studies will have broad clinical implications for the treatment of liver diseases[unreadable] in which regulation of hepatic growth is impaired, including cirrhosis and hepatocellular carcinoma, as well[unreadable] as associated metabolic syndromes such as non-alcoholic fatty liver disease (NAFLD).[unreadable]